Proton-Coupled Oligopeptide Transporters (PEPTs) are specialized proteins found on the surface membranes of various cells throughout the body. These proteins function as transporters, facilitating the movement of small peptides, specifically dipeptides (two amino acids linked together) and tripeptides (three amino acids linked together), from outside the cell to its interior. PEPTs belong to a larger group of proteins known as the Solute Carrier Transporter (SLC) superfamily, which is responsible for mediating the uptake of various substances, both those produced by the body and those from external sources. The transport activity of PEPTs is energized by an electrochemical proton gradient, meaning they move peptides into the cell by simultaneously moving protons down their concentration gradient.
The Two Main Types of PEPT
Two primary forms of these transporters, PEPT1 and PEPT2, have been extensively studied due to their significant roles in human physiology and pharmacology. These two isoforms exhibit distinct characteristics regarding their transport capabilities. PEPT1 is a high-capacity, low-affinity transporter, meaning it can move a large quantity of peptides but requires higher concentrations of those peptides to operate efficiently. Conversely, PEPT2 is a low-capacity, high-affinity transporter, moving smaller amounts of peptides effectively even at very low peptide concentrations.
The distribution of these transporters within the body also differs markedly. PEPT1 is predominantly located in the apical membrane of enterocytes, the specialized cells lining the small intestine, where it plays a significant role in nutrient absorption. PEPT2, however, displays a broader expression pattern across various tissues. It is found in the kidneys, the choroid plexus within the brain, and the lungs.
Role in Nutrient Absorption
The small intestine is the primary site for nutrient absorption, and PEPT1 plays a central role in this process for dietary proteins. When we consume proteins, they are broken down by digestive enzymes into individual amino acids and small di- and tripeptides within the intestinal lumen. While some amino acids are absorbed directly, PEPT1 is the main transporter for the uptake of these dipeptides and tripeptides into the intestinal epithelial cells.
This proton-coupled transport mechanism allows for a highly efficient absorption of protein digestion products. PEPT1 can transport a wide array of these small peptides, including over 400 different dipeptides and 8,000 tripeptides, contributing significantly to the body’s nitrogen supply. Once inside the enterocytes, these absorbed di- and tripeptides are hydrolyzed by intracellular peptidases into free amino acids. These individual amino acids are then transported across the basolateral membrane of the enterocytes and into the bloodstream.
Importance in Drug Delivery
The unique transport properties of PEPTs have been strategically leveraged by the pharmaceutical industry to enhance the absorption of certain medications. Many drug molecules are designed to mimic the structure of natural peptides or are formulated as prodrugs that contain a peptide-like bond. This structural similarity allows PEPT1, particularly in the small intestine, to recognize and transport these drugs from the intestinal lumen into the systemic circulation. This mechanism can significantly improve the oral bioavailability of drugs that would otherwise be poorly absorbed.
Several classes of drugs rely on PEPT-mediated transport for their effectiveness. For instance, many beta-lactam antibiotics, such as ampicillin, cephalexin, and amoxicillin, are transported into the body via PEPT1. Similarly, certain angiotensin-converting enzyme (ACE) inhibitors, like enalapril and captopril, utilize these transporters for their absorption. Antiviral drugs, such as valacyclovir, also benefit from PEPT1-mediated uptake. Understanding the molecular structure of PEPTs, including PEPT1, assists pharmacologists in designing new drugs with improved absorption characteristics.
Function Beyond the Gut
While PEPTs are well-known for their roles in the gut, their functions extend to other bodily systems, playing different yet equally important roles. In the kidneys, both PEPT1 and PEPT2 contribute to the reabsorption of small peptides from the glomerular filtrate. The kidneys filter a large volume of blood, and this filtrate contains small peptides that would otherwise be lost in the urine. PEPTs, particularly PEPT2 due to its high affinity, work to recover these valuable peptide-bound amino acids, preventing their excretion and helping to conserve the body’s nitrogen balance.
Beyond the kidneys, PEPT2 also has a presence in the brain, specifically within the choroid plexus, which forms part of the blood-cerebrospinal fluid barrier. Here, PEPT2 can facilitate the efflux of certain peptidomimetic drugs and neuropeptides from the cerebrospinal fluid into the bloodstream. This outward transport mechanism helps to regulate the levels of various substances in the brain’s extracellular environment, thereby contributing to the maintenance of neuropeptide homeostasis and restricting the entry of some compounds into the central nervous system.